DESCRIPTION: (Applicant's Abstract) 'Stimulant' Abuse has debilitating consequences for individuals, families, society. Opioid abuse is similarly problematic. The drugs in combination form another 'drug problem'. IV abuse presents direct risks of blood borne infection. Stimulant abuse in social settings, particularly combined with alcohol, increases risky sexual behavior (STDs, HIV) and accidents of all sorts. The sum produces the debilitating direct and indirect result A medication armamentarium exists for opiate abuse, but it is only in development for stimulant abuse. The competing continuation Center application includes an Administrative/Scientific Coordinating Core, and 4 integrated component projects. Our Center's focus is development of agonist medications, from 'clean' specific receptor agonists, 1-dopa, through 'dirty', multi- mechanism agonists, amphetamine analogs as a prototype. Also important are dual stimulant+opiate abuse studies with a mg/kg opiate agonist dose as the treatment baseline. We use a systematic sequential strategy with a GCRC drug interaction studies in support of Clinical Trials of direct Efficacy, and Clinical Trials of Efficacy/Effectiveness (joint action of medication+behavior therapy). Trials are conducted using standard Large N Randomized Clinical Trials (RCT) and innovative Small N designs, evaluated with advanced data analytic procedures. The developing Small N designs are cost effective, and efficient, exposing fewer subjects to medications in Phase 11. RCTs subserve FDA approvals. All studies are rigorously conducted with RFA specified instruments, state of the science chemistry, clinical, behavior therapy, and data analytic procedures, all well established at this site. The Substance Abuse Research Center, University of Texas-Houston, has conducted innovative, integrate research for a decade. With broad scientific expertise we examine issues from chemistry to clinic. Research domains include analytical neurochemistry, preclinical psychopharmacology, human psychopharmacology, clinic, and the GCRC. The group works in the unusually supportive and diverse environment of the Texas Medical Center (TMC) with its many research and clinical institutions (65,000 employees), located centrally in Houston, 4th largest US city. Thus, this Center serves the TMC, community, and region as a resource, while conducting the innovative research described in the application. Further, the Center is devoted to collaborating with NIDA/MDD and the other MDD Centers and this is evidenced in the application and history. In sum, this application provides unique strengths for the conduct of substance abuse medications development research.